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Abstract

The African endemic form of Burkitt Lymphoma (BL) is one of the most common pediatric malignancies in sub-Saharan Africa. BL is particularly prevalent in certain geographic regions, likely due to both environmental and genetic influences. BL is a malignancy of antigen-experienced, germinal center centroblasts. Normal B cells express a functional B cell receptor on their surface that is generated from ordered chromosomal rearrangements at the immunoglobulin (Ig) loci. We performed high-throughput sequencing on genomic DNA extracted from primary BL tumors. The sequencing was focused on the Ig loci from three independent BL patient cohorts to assess the complete repertoire of Ig rearrangements contained in BL tumors. This analysis demonstrated that 55 of 69 tumors harbored a clonal Ig heavy chain (IGH) repertoire. Amongst clonal tumors, a second rearranged IGH allele was only detected in 11 cases, suggesting widespread monoallelic IGH rearrangements in BL tumors. Most tumors were characterized by extensive Ig sequence variation; hundreds of related, but unique, nucleotide sequences were detected in most tumors. These sequence families were associated with both complete VDJ rearrangements and incomplete DJ rearrangements, demonstrating the activity of active mutational processes at the Ig loci in BL tumors. IGH sequences are highly specific and can serve as a molecular barcode for each B cell. Assessment of matched patient blood samples demonstrated that tumor-associated IGH sequences were regularly detected in circulation at diagnosis. Positive detection of circulating tumor DNA at diagnosis was associated with inferior patient survival than when tumor DNA was not detected, suggesting that tumor-specific IGH sequences may have prognostic value for BL patients. The data presented in this dissertation suggest an alternative model of BL pathogenesis and assess the utility of IGH sequences as a biomarker for BL detection. The goal of this work is to expand the BL research repertoire to provide insights that will contribute to disease prevention efforts and ultimately improve the outcome for BL patients.